Pancreatic cancer is a highly lethal malignancy that presents multiple technical challenges for genomic studies. Next-generation sequencing and its applications have proven successful in the study of other tumour types, unravelling the interplay between DNA and RNA changes that are unique to the tumour. This Review outlines the genomic studies performed to date that have explored the somatic alterations of pancreatic cancer genomes, setting the stage for the introduction of our current technological capabilities. In spite of several challenging aspects posed by pancreatic tumours in particular and clinical sequencing-based diagnostics in general, next-generation sequencing and analysis can now be used in experiments relating to the treatment of patients with this disease. As a means to improve patient outcomes, the application of comprehensive next-generation sequencing and analysis to the genomes of patients with pancreatic cancer to identify therapeutic options is proposed.